The aim of this application is to prospectively evaluate dietary polyphenols in relation to risk of type 2 diabetes using data on dietary intakes as well as urinary biomarkers. Studies of diet and risk of type 2 diabetes have focused on macronutrients, vitamins and minerals. In recent years, however, there has been mounting evidence in support of beneficial effects of polyphenols-rich foods including whole grains, coffee, tea, and dark chocolate on glucose metabolism. Mechanistic and animal studies have shown that various polyphenols have antioxidant and phytoestrogen properties, delay intestinal glucose uptake, and affect signaling insulin signaling pathways. However, few studies have examined polyphenol intakes in relation to risk of type 2 diabetes. The recent availability of new food composition data and accurate urinary biomarkers allows the comprehensive evaluation of polyphenols in large-scale prospective studies. The Nurses'Health Studies (NHS) I and II are ongoing prospective cohort studies with over 200,000 participants on whom extremely detailed information on diet, lifestyle factors, and diseases has been collected. In these cohorts, more than 6,000 incident cases of type 2 diabetes have been ascertained. Morning spot urine samples have been collected in 48,345 NHS participants between 1997 and 2001. Among these participants, we will conduct a nested case-control study including 1,060 incident type 2 diabetes cases and 1,060 matched controls. We propose to study: 1). Urinary biomarkers of dietary polyphenols in relation to risk of type 2 diabetes. We will measure twelve polyphenols including enterolignans, phenolic acids, and flavonoids. 2). Polyphenol intakes in relation to disease biomarkers (sex hormones, and markers of inflammation, endothelial dysfunction and insulin resistance) that may mediate effects on the development of type 2 diabetes. 3). Intakes of the various classes of polyphenols in relation to risk of type 2 diabetes in the full NHS cohorts. The approaches using biomarkers and dietary intakes are complementary as they incorporate variation in bioavailability or reflect the effects of intakes per se. These large well-defined prospective cohorts with availability of detailed information on dietary intake in combination with urine samples and high-throughput measurement of biomarkers provide a unique and extremely cost- effective opportunity to identify novel dietary factors affecting risk of type 2 diabetes. PUBLIC HEALTH RELEVANCE: Because type 2 diabetes is a serious and chronic disease with a rapidly increasing prevalence, the importance of preventative action is widely acknowledged. Findings of the proposed application can be used to develop more effective dietary advice and to make changes in food composition to contribute to the prevention of type 2 diabetes.